Interest in the physiological activities and potential clinical uses of the pineal hormone melatonin (N-acetyl-5-methoxytryptamine) has grown enormously in recent years. The hormone has been implicated in the regulation of phenomena as diverse as the sleep-wake cycle, depression, sexual urge, neuroimmunomodulation, mammary cancer, etc. We have mounted the first systematic program to develop agonists and antagonists for the hormone, and affinity labels for its multiple receptors. 2-Iodo- and 2- bromelatonin can now be made by one-step syntheses and bind to the known receptor much more effectively than melantonin itself. Our new and greatly improved syntheses for these compounds will also facilitate preparation of labelled compounds for radioimmune assay. The superior binding implies that the receptor contains a large lipophilic hole, which may bind other 2-substituted melatonin analogues even more effectively. Synthetic methods are now being developed to obtain such analogues by radical alkylation procedures, which proved so effective in producing 2- alkylhistidines and histamines. Studies have continued on the use of oxindoles as inhibitors of aldose reductase as a means to control diabetic retinopathy. We have now achieved inhibitory potencies (in vitro) equal to, or greater than, those of the best inhibitors gene-rated by pharmaceutical industry, but have totally eliminated incorporation into the structures of strong allergy- inducing hydantoins. New work involves the development of prodrugs suitable for oral administration, based on the slow release of malonic acid structures from their esters by nonenzymatic hydrolysis. Several years ago, we made a concerted effort to obtain 2-fluoroindoles by halogen exchange with 2-bromoindoles, but were unsuccessful. Direct fluorination by use of new fluorinating agents has now been found surprisingly successful and such compounds (2-fluoroserotonin, 2- fluoromelationin) are anticipated to find application as affinity labels, analogues of peptide hormones and PET scanning reagents (since the introduction of radiolabel requires only one step).